Project Summary/Abstract Dental caries, the most common, chronic, infectious childhood disease, has a substantial impact on children?s quality of life. The high prevalence of dental caries that persists despite its preventability necessitates improvement in diagnostics and therapeutic interventions for this young and vulnerable population. Over the years, significant progress has been made in caries research. Despite these advances, research gaps remain, limiting the ability to answer two fundamental questions: 1) Why do not all individuals with elevated levels of Streptococcus mutans (Sm), an important infectious, cariogenic bacterium, develop caries? 2) How does host genetic variation contribute to the susceptibility to dental caries? The former continues to be a major enigma in the field of oral microbiology. Though host susceptibility has been recognized as an important determinant in medical infectious diseases, it remains an under-studied factor in caries research. Dr. Nini Tran, an Assistant Professor at the UCLA School of Dentistry, is a pediatric dentist-scientist with a well-rounded training and a long-standing commitment to a research career. The career development plan enables Dr. Tran to gain additional expertise in three areas: 1) Microbiology and microbiome research, 2) biostatistics and bioinformatics, 3) saliva diagnostics. Dr. Tran will be supported by an outstanding multidisciplinary mentoring team with expertise to cover all elements of her research and career development. Dr. David Wong, a pioneer in the field of saliva diagnostics, is her primary mentor; Dr. Wenyuan Shi, Dr. Jeff Miller, Dr. Renate Lux, Dr. Xuesong He, Dr. Floyd Dewhirst, and Dr. Ann Griffen are the leading microbiology and microbiome experts; Dr. David Elashoff provides biostatistics support, while Dr. Jeff McLean has expertise in next-generation sequencing and bioinformatics analyses. Through a tailored curriculum of courses, workshops and the proposed research, Dr. Tran will develop crucial skills to achieve her goal of becoming a successful independent clinician-scientist in the field of childhood caries diagnostics and therapeutics. This research investigates a discordant, preschool child population whose caries status contradicts what is expected based on their Sm level in comparison to the accordance counterpart. Integrating innovative study design and novel tools, the research plan aims to 1) characterize Sm strain individuality and its ecological relationship within different microbial communities, 2) explore salivary host biomarkers related to childhood caries, and 3) validate Sm-associated microbial virulence signatures and host salivary biomarkers for precise and comprehensive caries assessment. This research will generate the basis for R01 proposals, focusing on oral microbiome inter- species interaction, and host and oral microbial interaction related to childhood caries susceptibility, and the development of diagnostics and therapeutics for childhood caries. Finally, this award will position Dr. Tran to become a top tier pediatric dentist-scientist, and enable her to make a significant contribution to the field of pediatric dentistry.